NF-κB perturbation reveals unique immunomodulatory functions in Prx1 + Fibroblasts that Promote Development of Atopic Dermatitis

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor кB (NF-кB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-кB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-кB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions. © 2022 The Authors, some rights reserve

Flight Performance Handbook for Orbital Operations: Orbital Mechanics and Astrodynamics Formulae, Theorems, Techniques, and Applications

This handbook provides parametric data useful both to the space vehicle designer and mission analyst. It provides numerical and analytical relationships between missions and gross vehicle characteristics as a function of performance parameters. The effects of missile constraints and gross guidance limitations plus operational constraints such as launch site location, tracking net location, orbit visibility and mission on trajectory and orbit design parameters are exhibited. The influence of state-of- the-art applications of solar power as compared to future applications of nuclear power on orbit design parameters, such as eclipse time, are among the parameters included in the study. The principal aim, however, is in providing the analyst with useful parametric design information to cover the general area of earth satellite missions in the region of near-earth to cislunar space and beyond and from injection to atmospheric entry and controlled descent. The chapters are organized around the central idea of orbital operations in the 1961-1969 era with emphasis on parametric flight mechanics studies for ascent phase and parking orbits, transfer maneuvers, rendezvous maneuver, operational orbit considerations, and operational orbit control. The results are based almost entirely on the principles of flight and celestial mechanics. Numerous practical examples have been worked out in detail. This is especially important where it has been difficult or impossible to represent all possible variations of the parameters. The handbook contains analytical formulae and sufficient textual material to permit their proper use. The analytic methods consist of both exact and rapid, approximate methods. Scores of tables, working graphs and illustrations amplify the mathematical models which, together with important facts and data, cover the engineering and scientific applications of orbital mechanics. Each of the five major chapters are arranged to provide a rapid review of an entire astrodynamic subject. By the use of compact graphical and tabular presentation the full scope of the material is made available in an easy-to-use style. Throughout the volume the analyst is shown, by means of suitable introductions, notes, authoritative examples, and cross-references the vital interrelation of the various orbital mechanics topics in the general field of earth satellites and satellite rendezvous. The handbook is designed to give the analyst rapid, reliable access to the mathematics of orbital mechanics needed for virtually any working requirements